2.1 Basic Dosing Information

The recommended dosing schedule for ORAVIG is the application of one 50 mg buccal tablet to the upper gum region (canine fossa) once daily for 14 consecutive days.

2.2 Administration Instructions

ORAVIG should be applied in the morning, after brushing the teeth. The tablet should be applied with dry hands. The rounded side surface of the tablet should be placed against the upper gum just above the incisor tooth (canine fossa) and held in place with slight pressure over the upper lip for 30 seconds to ensure adhesion. The tablet is round on one side for comfort, but either side of the tablet can be applied to the gum.

Once applied, ORAVIG stays in position and gradually dissolves. [ See Clinical Pharmacology (12.3)] Subsequent applications of ORAVIG should be made to alternate sides of the mouth. Before applying the next tablet, the patient should clear away any remaining tablet material. In addition,

• ORAVIG should not be crushed, chewed or swallowed.
• Food and drink can be taken normally when ORAVIG is in place but chewing gum should be avoided.
• If ORAVIG does not adhere or falls off within the first 6 hours, the same tablet should be repositioned immediately. If the tablet still does not adhere, a new tablet should be placed.
• If ORAVIG is swallowed within the first 6 hours, the patient should drink a glass of water and a new tablet should be applied only once.
• If ORAVIG falls off or is swallowed after it was in place for 6 hours or more, a new tablet should not be applied until the next regularly scheduled dose. [ see Patient Counseling Information (17)].

5.1 Hypersensitivity

Allergic reactions, including anaphylactic reactions and hypersensitivity, have been reported with the administration of miconazole products, including ORAVIG. Discontinue ORAVIG immediately at the first sign of hypersensitivity.

There is no information regarding cross-hypersensitivity between miconazole and other azole antifungal agents. Monitor patients with a history of hypersensitivity to azoles.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The overall safety of ORAVIG was assessed in 480 adult subjects: 315 HIV-infected subjects, 147 subjects with head and neck cancer, and 18 healthy subjects.

HIV Infected Patients
Two trials were conducted in immunocompromised HIV-infected patients: one randomized, double-blind, double-dummy, active-controlled design (N = 290 ORAVIG, 287 control) and one non-comparative trial (N = 25).

In the randomized, double blind trial (Study 1), 290 HIV infected subjects used ORAVIG once daily for 14 days, and 287 subjects used 10 mg clotrimazole troches five times daily for 14 days. Adverse reactions occurring in ≥ 2% of patients in either treatment are presented in Table 1.

Table 1 Adverse Reactions (Treatment-Emergent) Occurring in ≥ 2% of HIV-Infected Patients in the Controlled Clinical Trial

Overall local adverse reactions, including oral discomfort, oral burning, oral pain, gingival pain, gingival swelling, gingival pruritis, tongue ulceration, mouth ulceration, glossodynia, dry mouth, application site pain or discomfort, toothache, loss of taste, and altered taste, were reported by 35 (12.1%) patients who received miconazole buccal tablet compared to 27 (9.4%) patients who received clotrimazole troches.

Head and Neck Cancer Patients
In the randomized, open-label comparative trial of oropharyngeal candidiasis in patients with head and neck cancer who had received radiation therapy (Study 2), 147 patients used ORAVIG once daily for 14 days and 147 patients used 125 mg of miconazole oral gel four times daily for 14 days. Adverse reactions occurring in ≥2% of patients in either arm are listed in Table 2.

Table 2: Adverse Reactions (Treatment-Emergent) Occurring in ≥ 2% of Patients with Head and Neck Cancer who had Received Radiation Therapy (Controlled Clinical Trial)

Overall local adverse reactions, including oral discomfort, oral pain, dry mouth, glossodynia, loss of taste, altered taste, tongue ulceration, mouth ulceration, tooth disorder, and application site discomfort or pain, were experienced by 14 (9.5%) patients who used ORAVIG compared to 16 (10.9%) patients who used miconazole gel.

Overall ORAVIG Safety Experience In Patients and Healthy Subjects
Adverse reactions reported in the overall safety database of 480 subjects who received miconazole buccal tablet is listed in Table 3.

Table 3 Adverse Reactions Reported in ≥ 2% of Patients and Healthy Subjects who Received ORAVIG in Clinical Trials

Discontinuation of ORAVIG due to adverse drug reactions occurred in 0.6% overall.

7.1 Warfarin

Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Cases of bleeding and bruising following the concomitant use of warfarin and topical, intravaginal, or oral miconazole were reported. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if ORAVIG is administered concomitantly with warfarin. Also monitor for evidence of bleeding.

7.2 Drugs Metabolized Through CYP 2C9 and 3A4

No formal drug interaction studies have been performed with ORAVIG. Miconazole is a known inhibitor of CYP2C9 and CYP3A4. Although the systemic absorption of miconazole following ORAVIG administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP2C9 and CYP3A4 such as oral hypoglycemics, phenytoin, or ergot alkaloids cannot be ruled out.

8.1 Pregnancy

Risk Summary

Based on findings from animal data, ORAVIG may cause fetal harm when administered to pregnant women. There are no available data on ORAVIG use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, prolonged gestation, dystocia and/or increased number of resorptions were observed after oral administration of miconazole nitrate during organogenesis to pregnant rats and rabbits. (See Data). Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data:

Miconazole nitrate administered orally at doses of 80 mg/kg/day or higher to pregnant rats or rabbits crossed the placenta and resulted in embryo- and fetotoxicity, including increased fetal resorptions. These doses also resulted in prolonged gestation and dystocia in rats, but not in rabbits. Embryofetotoxicity was not observed in intravenous studies with miconazole at lower doses of 40 mg/kg/day in rats and 20 mg/kg/day in rabbits, which are approximately 8 times higher than the dose a patient would receive if she swallowed an ORAVIG buccal tablet, based on body surface area comparisons. Teratogenicity was not reported in any animal study with miconazole.

8.2 Lactation

Risk Summary

There is no available information on the presence of miconazole in human milk, or the effects on the breastfed child, or the effects on milk production following use of ORAVIG.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORAVIG and any potential adverse effects on the breastfed infant from ORAVIG or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of ORAVIG in pediatric patients below the age of 16 years have not been established. The ability of pediatric patients to comply with the application instructions has not been evaluated. Use in younger children is not recommended due to potential risk of choking.

8.5 Geriatric Use

Clinical studies of ORAVIG did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

Miconazole is metabolized by the liver. While miconazole systemic exposure is minimal following the application of ORAVIG, ORAVIG should be administered with caution in patients with hepatic impairment.

8.7 Renal Impairment

Less than 1% of miconazole is excreted as unchanged drug in the urine; therefore, no adjustment to therapy is necessary in patients with renal impairment.

12.1 Mechanism of Action

Miconazole is an antifungal drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption and Distribution

Salivary

Single dose application of ORAVIG containing 50 mg of miconazole to the buccal mucosa of 18 healthy volunteers provided mean maximum salivary concentrations of 15 mcg/mL at 7 hours after application of the tablet. This provided an average saliva exposure to miconazole estimated from the AUC (0-24h) of 55.23 mcg·h/mL. The pharmacokinetic parameters of miconazole in the saliva of healthy volunteers are provided in Table 4.

Table 4: Pharmacokinetic (PK) Parameters of Miconazole in Saliva Following Application of a Single ORAVIG 50 mg Tablet in Healthy Volunteers (N = 18)

*Median

In healthy volunteers, the duration of buccal adhesion was on average 15 hours following a single dose application of ORAVIG 50 mg.

Plasma

Plasma concentrations of miconazole were below the lower limit of quantification (0.4 mcg/mL) in 157/162 (97%) samples from healthy volunteers following single-dose application of ORAVIG 50 mg. Measurable plasma concentrations ranged from 0.5 to 0.83 mcg/mL.

Plasma concentrations of miconazole evaluated after 7 days of treatment in 40 HIV-positive patients were all below the limit of quantification (0.1 mcg/mL).

Metabolism and Excretion

Most of the absorbed miconazole is metabolized by the liver with less than 1% of the administered dose found unchanged in urine. In healthy volunteers, the terminal half-life is 24 hours following systemic administration. There are no active metabolites of miconazole.

Food Effect

There was no formal food effect study conducted with ORAVIG; however, in clinical studies patients were allowed to eat and drink while taking ORAVIG.

12.4 Microbiology

Mechanism of Action

Miconazole inhibits the enzyme cytochrome P450 14α-demethylase which leads to inhibition of ergosterol synthesis, an essential component of the fungal cell membrane. Miconazole also affects the synthesis of triglycerides and fatty acids and inhibits oxidative and peroxidative enzymes, increasing the amount of reactive oxygen species within the cell.

Antimicrobial Activity

Miconazole is active against Candidaalbicans,C. parapsilosis and C. tropicalis. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established.

Resistance

In vitro studies have shown that some Candida strains that demonstrate reduced susceptibility to one antifungal azole may also exhibit reduced susceptibility to other azoles suggesting cross-resistance.

Clinically relevant resistance to systemically utilized triazoles may occur in Candida species. Resistance may occur by multiple mechanisms such as changes in amino acids and/or in the regulation of the target enzyme and of a variety of efflux pump proteins. Multiple mechanisms may co‑exist in the same isolate. Resistance breakpoints, correlating in vitro activity with clinical efficacy, have not been established for miconazole.

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenicity studies with miconazole have not been conducted.
Miconazole nitrate was not genotoxic when tested in vitro in a bacterial reverse mutation (Ames) assay or in an in vivo mouse bone marrow micronucleus test. Intraperitoneal injections of miconazole to mice induced chromosomal aberrations in spermatocytes and bone marrow cells, and morphologic abnormalities in sperm at doses similar to or below clinical doses. However, no impairment of fertility was observed in intravenous studies with miconazole at 40 mg/kg/day in rats or 20 mg/kg/day in rabbits, which are approximately 8 times higher than the dose a patient would receive if she swallowed an ORAVIG buccal tablet, based on body surface area comparisons.

13.2 Animal Pharmacology & OR Toxicology

Local tolerance studies (LLNA sensitization test and tolerance study on the jugal mucosa of hamster) did not reveal any toxicity.